Combination Therapies and Methods Using Anti-CD3 Modulating Agents and Anti-IL-6 Antagonists

Abstract

This invention relates generally to compositions that contain multiple modulating agents, e.g., multiple modulating agents that target CD3 on T cells and neutralize one or more biological activities of interleukin-6 (IL-6), such as CD3 modulators including anti-CD3 antibodies and anti-IL-6 antagonists including anti-IL-6 antibodies, anti-IL-6R antagonists including anti-IL-6R antibodies, and/or anti-IL-6/IL-6R complex antagonists including anti-IL-6/IL-6R binding antibodies, and methods of using these compositions in the treatment, amelioration and/or prevention of relapse of an autoimmune disease.

What is claimed is: 
     
         1 . A method of treating, delaying the progression of, preventing a relapse of, or alleviating a symptom of an autoimmune disease, the method comprising administering a combination of modulating agents to a subject in need thereof in an amount sufficient to treat, delay the progression of, prevent a relapse of, or alleviate the symptom of the autoimmune disease in the subject, wherein said combination of modulating agents comprises a modulating agent that binds to CD3 and an antagonist that binds to IL-6, IL-6R and/or IL-6Rc. 
     
     
         2 . The method of  claim 1 , wherein the modulator of CD3 is an anti-CD3 antibody. 
     
     
         3 . The method of  claim 2 , wherein the anti-CD3 antibody is a monoclonal antibody. 
     
     
         4 . The method of  claim 2 , wherein the anti-CD3 antibody is a mouse, chimeric, humanized, domain or fully human monoclonal antibody. 
     
     
         5 . The method of  claim 1 , wherein the antagonist of IL-6, IL-6R and/or IL-6Rc is an anti IL-6, anti-IL-6R and/or anti-IL-6Rc antibody. 
     
     
         6 . The method of  claim 5 , wherein the anti IL-6, anti-IL-6R and/or anti-IL-6Rc antibody is a monoclonal antibody. 
     
     
         7 . The method of  claim 5 , wherein the anti IL-6, anti-IL-6R and/or anti-IL-6Rc antibody is a chimeric, humanized, domain or fully human monoclonal antibody. 
     
     
         8 . The method of  claim 1 , wherein the antagonist of IL-6, IL-6R and/or IL-6Rc is soluble gp130. 
     
     
         9 . The method of  claim 1 , wherein the subject is a human. 
     
     
         10 . The method of  claim 1 , wherein the autoimmune disease is rheumatoid arthritis. 
     
     
         11 . The method of  claim 1 , wherein the autoimmune disease is Crohn's disease. 
     
     
         12 . The method of  claim 1 , wherein the autoimmune disease is selected from the group consisting of ankylosing spondylitis, asthma, Behcet's syndrome, glomerular nephritis, graft-versus-host disease, grave's disease, Hashimoto's thyroiditis, hidradenitis suppurativa, juvenile rheumatoid arthritis, luminal and fistulizing Crohn's disease, polyarticular juvenile arthritis, polymyositis/myositis/giant cell myocarditis and dermatomyositis, psoriasis, psoriatic arthritis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, undifferentiated polyarthritis, and uveitis. 
     
     
         13 . The method of  claim 1 , wherein the CD3 modulating agent and the antagonist of IL-6, IL-6R and/or the IL-6Rc are present in the combination in an amount sufficient to produce a synergistic inhibitory effect on one or more biological activities of IL-6, IL-6R and/or IL-6Rc in said subject. 
     
     
         14 . The method of  claim 4 , wherein the anti-CD3 antibody is a fully human anti-CD3 monoclonal antibody comprising a heavy chain CDR1 having the amino acid sequence GYGMH (SEQ ID NO: 1), a heavy chain CDR2 having the amino acid sequence VIWYDGSKKYYVDSVKG (SEQ ID NO: 2), a heavy chain CDR3 having the amino acid sequence QMGYWHFDL (SEQ ID NO: 3), a light chain CDR1 having the amino acid sequence RASQSVSSYLA (SEQ ID NO: 4), a light chain CDR2 having the amino acid sequence DASNRAT (SEQ ID NO: 5), and a light chain CDR3 having the amino acid sequence QQRSNWPPLT (SEQ ID NO: 6). 
     
     
         15 . The method of  claim 14 , wherein the antibody further comprises a mutation in the heavy chain at an amino acid residue at position 234, 235, 265, or 297 or combinations thereof, and reduces the release of cytokines from a T-cell. 
     
     
         16 . The method of  claim 15 , wherein said mutation results in an alanine or glutamic acid residue at said position. 
     
     
         17 . The method of  claim 16 , wherein the antibody is an IgG1 isotype and contains at least a first mutation at position 234 and a second mutation at position 235, wherein said first mutation results in an alanine residue at position 234 and said second mutation results in a glutamic acid residue at position 235. 
     
     
         18 . The method of  claim 14 , wherein the antibody further comprises a variable heavy chain region comprising the amino acid sequence of QVQLVESGGGVVQPGRSLRLSCAASGFKFS GYGMHWVRQAPGKGLEWVAVIWYDGSKKYYVDSVKGRFTISRDNSKNTLYLQMNSL RAEDTAVYYCARQMGYWHFDLWGRGTLVTVSS (SEQ ID NO: 8) and a variable light chain region comprising the amino acid sequence of EIVLTQSPATLSLSPGERATLSCRASQ SVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYY CQQRSNWPPLTFGGGTKVEIK (SEQ ID NO: 10).